Alzheimer's disease (AD) and progressive supranuclear (PSP) are neurodegenerative diseases with high medical unmet needs, high cost for the societies' health systems, and high burden for the families affected. AD clinical signs include loss of memory, cognition, reasoning, judgment and emotional stability and ultimately death. PSP involves serious and progressive gait control and balance issues, falls, vertical eyes movement disturbances, cognitive problems, depression, apathy, and mild dementia. Late symptoms include blurring of vision, uncontrolled eye movement, slurred speech, difficulty swallowing and death.
For more than a decade AD disease modification programs have targeted the amyloid-beta-peptide through various mechanisms. In contrast, much less progress has been made in addressing intracellular Tau pathology, the second major hallmark for AD. Neurofibrillary inclusions or tangles containing aggregated, hyperphosphorylated Tau are defining characteristics of AD pathology and a number of other tauopathies, including PSP.
In these diseases there is a strong correlation between symptomatic progression and the level and distribution of intraneural Tau aggregates. In AD neuronal Tau tangles first appear in the transentorhinal cortex, from where they spread to the hippocampus and neocortex. The tangles observed in AD neurons consist of hyperphosphorylated, aggregated insoluble Tau. Direct toxic effects of the pathological Tau species and/or loss of axonal transport due to sequestration of functional Tau into hyperphosphorylated and aggregated forms, which are no longer capable of supporting axonal transport, have been proposed to contribute to the disease.
In its non-pathological state, Tau is a highly soluble cytoplasmic microtubule-binding protein, which occurs in the human central nervous system (CNS) in 6 main isoforms due to alternative splicing, ranging from 352 to 441 amino acids in length. These isoforms can have zero, one or two N-terminal inserts (0N, 1N, 2N), and either three or four C-terminal “repeat” sequences (3R or 4R). These 30-32 amino acid C-terminal repeat sequences, R1, R2, R3 and R4, together constitute the Tau microtubule-binding region (MTBR). Indeed the main role of Tau is believed to be in the assembly and stabilization of axonal microtubules. Microtubules form tracks for axonal transport and cytoskeletal elements for cell growth (Clavaguera et al., Brain Pathology 23 (2013) 342-349). Three Tau isoforms have been demonstrated to contain three microtubule binding regions (MTBR):                isoform 4, also referred to as 3R0N, NCBI Reference Sequence NP 058525.1 (352 amino acid),        isoform 7, also referred to 3R1N, NCBI Reference Sequence NP 001190180.1 (381 amino acid)        isoform 8, also referred to as 3R2N, NCBI Reference Sequence NP 001190181.1 (410 amino acid).        
Whereas the other three Tau isoforms contain four MTBRs:                isoform 2, also referred to as 4R2N, NCBI Reference Sequence NP 005901.2 (441 amino acid),        isoform 3, also referred to as 4R0N, NCBI Reference Sequence NP 058518.1 (383 amino acid), and        isoform 5, also referred to as 4R1N, NCBI Reference Sequence NP 001116539.1 (412 amino acid).        
Tau contains 85 potential serine (S), threonine (T), and tyrosine (Y) phosphorylation sites. Many of the phosphorylated residues on Tau are found in the proline-rich domain of Tau, flanking the microtubule-binding domain. All six Tau isoforms are present in normal mature human brain, and at this stage Tau phosphorylation is relatively reduced (Noble et al., 2013 Front Neurol. 2013; 4: 83). In the various tauopathies, deposited Tau in pathological lesions is invariably highly phosphorylated. Phospho-Serine202 and phosphor-Threonine205 have been detected in aggregated Tau from brain samples and cerebrospinal fluid from PSP and AD patients (Buée et al., Brain Research Reviews 33 (2000) 95-130; Wray et al J Neurochem. 2008 Jun. 1; 105(6):2343-52; Hanger et al., J Biol Chem. 2007 Aug. 10; 282(32):23645-54; Maccioni et al Neurobiol Aging. 2006 February; 27(2):237-44).
Only symptomatic treatments are currently available for these diseases with mild or no efficacy. No treatment is currently available for slowing or ideally stopping the development of the disease. Therefore there remains a need in the art for new compounds and compositions useful in the treatment of tauopathies.